(PQ6) Mesenchymal stem cell based and immunocompetent mouse models of HIV/AIDS KSHV-driven sarcomagenesis

卡波西肉瘤是一种与HIV/ AIDS相关的恶性肿瘤

Kaposi’s sarcoma is an HIV/ AIDS associated malignancy that in spite of the implementation of ART causes significant morbidity and mortality. Pathogenesis based design and testing of new therapeutic approaches are hampered by the paucity of models that reproduce KSHV oncogenesis in the HIV/AIDS setting. There are three major gaps to the experimental ability to model AIDS-KS in vitro and in vivo for translational and preclinical research. 1) A continuous in vitro KSHV-infection to tumorigenesis model that could help dissect microenvironment contributions, and dissect viral and host contributions to viral oncogenesis 2) An in vitro and in vivo model where HIV contributions to KSHV-sarcomagenesis can be identified and studied 3) An immunocompetent model of KSHV-tumorigenesis that could be used to test immune-based therapies. The Mesri and Roy Labs collaboratively developed a comprehensive set of cell and animal models of KSHV-driven Kaposi’s sarcoma that include. I) A mesenchymal-stem cell KSHV- infection to tumorigenesis system--a “de novo” KSHV-induced sarcomagenesis in vitro and in vivo model, which is tightly dependent on the infected-cell microenvironment for tumorigenicity II) A set of mouse models in which KSHV tumorigenesis occurs and can be studied in the context of immunodeficiency, HIV-infection contributions to tumorigenesis and KSHV tumorspecific immunosuppression III) A unique model in which KSHV-infected tumors can be transplanted and grown in HIV infected Balb/c mice. In Aim (1) we will use the MSCs models study the role of KSHV and HIV interactions in viral oncogenesis of HIV/AIDS-KS. In Aim (2) we will determine the mechanisms whereby HIV infection promotes KSHV tumorigenicity in nude and immunocompetent mice. In Aim (3), we will use our model of KSHV-tumorigenesis in HIV infected immunocompetent mice as AIDS-KS preclinical model. We will be able to test immunological therapies to KS such as immunomodulatory molecules, antibody-targeted therapies and checkpoint inhibitor immunotherapies. The propose studies provide unique mouse models to study the role of KSHV HIV co-infection in the pathogenesis of HIV/AIDS-associated Kaposi’s sarcoma and will serve to pre-clinically evaluate novel AIDS-KS therapeutic treatments.